Method of delivering therapeutic agents to the urethra and an urethral suppository

ABSTRACT

A method of delivering one or more therapeutic agents comprising providing a suppository comprising one or more therapeutic agents and a biocompatible carrier medium and shaped to be capable of cooperating with the periurethral musculature to retain the suppository in place in the urethra, inserting the suppository into the urethra, and retaining the suppository within the urethra by the action of the periurethral musculature for a period of time sufficient to permit the therapeutic agent to diffuse substantially into the urethra, the referred suppository comprising a shaft having a first end and a second end and shaped to be capable of cooperating with the action of the periurethral musculature to retain the suppository within the urethra and a substantially ellipsoidal knob extending from the second end of the shaft and sized to prevent insertion into the urethra.

FIELD OF THE INVENTION

[0001] This invention relates to a method of delivering therapeuticagents to the urethra, bladder and related structures and an urethralsuppository for use in delivering therapeutic agents thereto.

[0002] In the treatment of various ailments affecting the urethra,bladder and related structures, it is generally not desirable to delivertherapeutic agents systemically. When delivery of such agents isaccomplished in a systemic fashion such as, for example, orally of byway of a remote intravenous, intramuscular, subcutaneous or transdermalroute, relatively high dosages are required in order to deliver anamount to the affected areas sufficient to have the desired therapeuticeffect. The requirement for such relatively high dosages results fromthe dilution and dissipation effects attendant to such delivery methodsas well as the loss of efficacy that can result from biochemicalinteractions between the therapeutic agent and unrelated systems.Further, due to the relatively high dosages required by systemicdelivery methods, the risks of triggering both adverse reactions andunwanted side effects are increased. Accordingly, it is known to employdelivery methods which provide for the local application of therapeuticagents in the treatment of urethral, bladder and related ailments inorder to administer relatively small dosages to achieve delivery ofrelatively high concentrations of such agents to the affected areas.

[0003] While the local application of therapeutic agents permits the useof smaller dosages, and can avoid certain of the drawbacks associatedwith systemic delivery methods as mentioned hereinabove, a different setof problems arise with respect thereto. In the context of treatingconditions affecting the urethra, bladder and related structures, forexample, it is of primary importance that the local application oftherapeutic agents be accomplished in a manner compatible with theanatomical structures involved. Accordingly, it is known to employsuppositories as delivery devices for therapeutic agents. Suchsuppositories are designed to be inserted into the urethra and torelease therapeutic agents contained therein or applied thereon to themucosal lining of the urethra. The release of therapeutic agents occursupon liquefaction of the suppository which results from the transfer tothe suppository of the body heat of the patient into whose urethra thesuppository has been placed.

[0004] Various prior art suppositories, however, have been designed insuch a manner that they are difficult to retain in position within theurethra where the precise delivery of therapeutic agents is desired.Experience has shown that such suppositories tend either to advanceinwardly into the bladder or to be expelled out of the urethra prior tothe complete decomposition within the urethra. In either case, thedesired result of a precise placement of the specific dosage of theselected therapeutic agents within the urethra is not realized.

REPORTED DEVELOPMENTS

[0005] In order to address these shortcomings, it is known to configureurethral suppositories in the form disclosed in U.S. Pat. No. 5,085,650to Giglio (the '650 patent). The '650 patent discloses an urethralsuppository comprising a bulbous head and a conical tail joined by anarrow cylindrical shaft. As taught by the '650 patent, upon insertionof the suppository into the urethra of a human female patient, thebulbous head thereof is advanced through the entire length of theurethra and penetrates into the bladder to anchor the suppository at thebladder neck. The conical tail of the suppository prevents the furtheradvance of the suppository into the bladder. More specifically, once thesuppository is positioned within the urethra, the portion of the bulboushead of the suppository which curves inwardly toward the shaft isdesigned to prevent the suppository from expulsion by its contact withthe bladder walls at the bladder neck where the bladder narrows to themeet the proximal end of the urethra. At the same time, the flaredportion of the conical tail, having an increasingly larger diameter thanthe shaft of the suppository as well as the urethra itself, is designedto prevent the suppository from overinsertion by contact with the edgesof the urethral orifice at the distal end thereof. It is through thiscombination of contact surfaces that the suppository disclosed in the'650 patent is intended to be held in position during the liquefactionthereof.

[0006] While suppositories configured with bulbous heads, conical tailsand narrow cylindrical shafts, as disclosed in the '650 patent, aid inthe placement and retention of suppositories within the urethra ascompared with purely cylindrical suppositories that lack such features,such configurations permit, nonetheless, some slippage and, moreover,present certain other disadvantages. Because retention of thesuppository is effected, in part, by the contact between the inwardlycurved portion of the bulbous head with the bladder neck, it is requiredthat the bulbous head of the suppository advance beyond the urethra andinvade into the bladder itself. As a result, where therapeutic agentsare infused throughout the material comprising the suppository, theportion of the dosage contained within the material comprising thebulbous head thereof is not positioned so that it is in direct physicalcontact with the mucosal lining of the urethra and thus is not absorbedreadily therein. As a result, the precise delivery of a specific dosagethrough absorption by the urethra cannot be realized effectively.Further, insofar as the conical tail section of the suppositorydisclosed in the '650 patent has a flat base, it is difficult tomanipulate after insertion as it provides no projections which can begrasped readily. Moreover, the roundness of the conical tail renders thedistal end of the suppository less than fully compatible with theanatomical structure of the labia. As a result, the comfort of thepatient is compromised.

[0007] The present invention relates to the provision of an improvedmethod for delivering a therapeutic agent to the urethra and an easilymanipulatable urethral suppository which is designed to overcomedisadvantages associated with prior art suppositories.

SUMMARY OF THE INVENTION

[0008] In accordance with one aspect of the present invention, there isprovided a method for delivering a therapeutic agent to the urethra,bladder and related structures comprising the steps of providing asuppository comprising one or more therapeutic agents and abiocompatible carrier medium and shaped to be capable of cooperatingwith the action of the periurethral musculature to retain thesuppository within the urethra, inserting the suppository into theurethra, and retaining the suppository within the urethra by the actionof the periurethral musculature for a period of time sufficient topermit the therapeutic agent to diffuse substantially into the urethra.The suppository utilized in the method of the present invention may beof any shape capable of being inserted into the human female urethra andof cooperating with the periurethral musculature in retaining thesuppository within the urethra.

[0009] In accordance with another aspect of the present invention, thereis provided an urethral suppository shaped to be capable of cooperatingwith the action of the periurethral musculature to retain thesuppository within the urethra. Preferably, the suppository comprises ashaft having a rounded first end tapering along a longitudinal axis to asecond end, and a substantially ellipsoidal knob extending from thesecond end of the shaft and sized to prevent insertion into the urethra,said shaft and knob comprising a composition of at least one therapeuticagent and a biocompatible carrier medium. More preferably, thesubstantially ellipsoidal knob of the suppository has a major axis whichis substantially perpendicular to the longitudinal axis of the shaft. Itis also preferred that the biocompatible carrier medium is capable offorming a relatively soft, pliable and smooth suppository so that theneed for a lubricant to aid insertion can be eliminated and the risk ofpatient discomfort can be minimized.

[0010] The tapered shaft of the preferred suppository of the presentinvention provides a profile to the suppository which is particularlywell suited to work in concert with the normal action of theperiurethral musculature found in human females. So configured, thenaturally occurring pressure exerted by the periurethral musculature ismost advantageously utilized in retaining the suppository entirelywithin the urethra. This retention permits the complete delivery of aprecise dosage of one or more therapeutic agents to the mucosal liningthereof without invasion into the bladder.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011]FIG. 1 shows a profile view of a preferred suppository of thepresent invention.

[0012]FIG. 2 shows a cross-sectional view of a preferred suppository ofthe present invention as shown from line 2-2 of FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION

[0013] The urethra of the adult human female is a substantially tubularstructure which serves as the outlet for urine from the bladder. Whilethe urethra of the adult human female has some degree of variation insize across any given population, it is generally about 3 to about 4.5centimeters in length and about 0.8 to about 1.5 centimeters in diameterupon full expansion. The flow of urine from bladder is controlled bycertain muscles which surround the urethra and exert forces inwardly toconstrict the urethra. It will be understood that as used herein themuscles which surround and impinge upon the urethra will be referred toherein collectively as the periurethral musculature.

[0014] The forces applied by the periurethral musculature, however, arenot exerted evenly along the length of the urethra. Rather, due to thephysical arrangement of the periurethral musculature with respect to theurethra, these forces are applied differentially. Considering an averageadult human female urethra of about 4 centimeters in 1 centimeterintervals beginning at the bladder, the forces exerted by theperiurethral musculature increase substantially from the first to thesecond centimeter, increase further to a maximum within the thirdcentimeter, and drop off significantly in the last centimeter. Thisprofile of urethral pressures is substantially the same from patient topatient as it is a direct consequence of the anatomical configurationand location of the human female periurethral musculature.

[0015] In view of this specific pressure profile, a key feature whichserves to retain the suppositories disclosed in the '650 patent withinthe urethra, namely the inwardly curving portion of the bulbous head, isdesigned to do so at a region of low urethral pressure. In contrast, thepresent invention takes advantage of the naturally occurring forcesexerted by the periurethral musculature in holding the suppository inplace. It is designed specifically to work in concert with thedistinctive pressure profile of the human female periurethralmusculature. As a result, slippage of the present suppository within theurethra is minimized and precise delivery of the therapeutic agentthereto is achieved.

[0016] The provision of a suitably shaped suppository is important tothe practice of the method of the present invention. While thesuppository utilized in the method of the present invention may beprovided in any of a variety of shapes which are capable of insertioninto the human female urethra, it is important that the shape of thesuppository also be such that it is capable of cooperating with thepressure profile of the human female periurethral musculature to securethe suppository within the urethra. More specifically, and as describedmore fully hereinabove, the periurethral musculature exerts inwardforces upon the urethra in a differential manner with the greatestinward forces being located at a region approximately three centimetersdistal to the bladder. Accordingly, it is important that the suppositoryprovided in the method of the present invention have a shape which, uponinsertion into the urethra, permits the region of greatest urethralpressure to impinge thereon in a manner which promotes the secureplacement and retention of the suppository within the urethra. In apreferred embodiment of the method of the present invention, thesuppository provided will be of a shape as shown substantially in FIGS.1 and 2.

[0017] The therapeutic agents suitable for use in the suppositoryprovided in the method of the present invention may be any of a widevariety of compounds, substances, pharmaceuticals, and the like whichare capable of being absorbed through the mucosal lining of the humanfemale urethra, either alone or in combination with biocompatibleabsorption aids, and which have been approved or which will be approvedfor the diagnosis, treatment, prophylaxis, cure or mitigation of anydisease of the urethra, bladder or associated structures. Suchtherapeutic agents include, without limitation, antibiotics,antimicrobials, antifungal agents, analgesics, steroidal andnon-steroidal antiinflammatory agents, hormones such as estrogen andprogesterone, mucous production stimulators such as pentosan polysulfatesold under the trademark Elmiron® by Alza Corporation, anti-spasmodicssuch as oxybutynin chloride sold under the trademark Ditropan® byHoechst Marion Roussel, Inc., and the like. The urethral suppositoriesemployed in the method of the present invention are particularly wellsuited to the treatment of various infections, incontinence, uninhibitedneurogenic or reflex neurogenic bladder (i.e., urgency, frequency,urinary leakage, urge incontinence, dysuria), and non-specificurethritis, as well as post-menopausal urethral and bladder symptoms.

[0018] The therapeutic agents suitable for use in the suppositoryprovided in the method of the present invention may also comprisecompounds or substances used in conjunction with medical procedures suchas catheterization, cystoscopy, or transurethral surgery. Suchtherapeutic agents include, for example, antimicrobials, steroidal andnon-steroidal anti-inflammatory agents, and topical anaesthetics such aslidocaine, procaine, benzocaine, xylocaine and the like.

[0019] The biocompatible carrier medium suitable for use in thesuppository employed in the method of the present invention may beselected from any of a wide variety of biocompatible materials which arecapable of being combined with the desired therapeutic agents. Withrespect to the physical characteristics of the biocompatible carriermedia, it is important that such media are capable of becomingsufficiently rigid at room temperature to be inserted into the humanfemale urethra and of liquefying within a relatively short period oftime upon insertion therein. Preferably, the biocompatible carriermedium is capable of being formed into relatively soft, pliable andsmooth suppository so that comfort of the patient and ease of use isoptimized. In certain preferred embodiments, the biocompatible carriermedium is also self-lubricating, water-soluble, substantiallynon-staining and substantially free of parabens.

[0020] Biocompatible carrier media suitable for use in the suppositoryprovided in the method of the present invention include a wide varietyof polymers which are soluble in body fluids such as, for example,vegetable gums such as carrageenan, modified celluloses such ashydroxypropylcellulose or hydroxypropylmethylcellulose, polyvinylalcohol, polyvinylpyrrolidone, polyacrylamide, polyethylene glycol,poly(phosphoester-urethanes), ethylenoxide polymers, and the like.Preferably, the biocompatible carrier medium is selected so that theentire mass thereof is completely liquified within the urethra withinabout 10 minutes, and even more preferably within about 5 minutes.

[0021] The concentration of therapeutic agents found in the suppositoryemployed in the method of the present invention will vary in accordancewith, among other things, the nature of the therapeutic agents, theirphysiologic role, the desired therapeutic effect, and the manner inwhich the therapeutic agents and the biocompatible carrier medium arecombined. Thus, for example, the concentration of female hormones, suchas estrogen or progesterone, will likely be different from theconcentration of an anaesthetic or dialator used in connection with theperformance of a medical procedure.

[0022] The insertion step of the method of the present invention may beaccomplished by any means suitable for effecting the placement of thesuppository within the urethra. Such means may include, for example,manual or instrument-assisted insertion either by a health careprofessional or the patient herself.

[0023] The urethral suppository of the present invention comprises atherapeutic agent and a biocompatible carrier medium which are combinedand formed into a shape suitable for insertion into the human femaleurethra and capable of cooperating with the action of the periurethralmusculature to retain the suppository within the urethra. While thetherapeutic agent or agents as well as the biocompatible carrier mediummay be selected from any of a wide variety of materials appropriate forinclusion in an urethral suppository as set forth more fullyhereinabove, it is important that the urethral suppository of thepresent invention have certain shape characteristics. It is by means ofthese shape characteristics that the urethral suppository of the presentinvention advantageously utilizes the action of the periurethralmusculature in securing the position of the suppository within theurethra, provides for ease of insertion and manipulation, and promotesthe comfort of the patient through compatibility with the externalstructures of the human female genital anatomy.

[0024] In accordance with a preferred embodiment of the presentinvention, and with reference to FIG. 1, the suppository 10 comprises ashaft 12 having a rounded first end 13 tapering along a longitudinalaxis 14 to a second end 15 and a substantially ellipsoidal knob 16 sizedto prevent insertion into the urethra which extends from the second end15 which has a major axis 17 wherein the major axis 17 of the knob 16 issubstantially perpendicular to the longitudinal axis 14 of the shaft 12.As shown in FIG. 2, the shaft 12 is substantially circular. It is bymeans of the tapering of the shaft 12 that retention substantiallyentirely within the urethra by cooperation with the periurethralmusculature is advantageously realized. More specifically, uponinsertion of the suppository into the urethra, the first end 13 (wherethe diameter of the shaft 12 is at its greatest) corresponds to theproximal end of the urethra (where the urethra meets the bladder) atwhich the force of the periurethral musculature is the lowest. As theforce exerted by the periurethral musculature increases from a minimumat the proximal end of the urethra to a maximum at about threecentimeters distal thereto, the diameter of the shaft 12 decreases. Thetapering of the shaft 12 continues to the second end 15 at which asubstantially ellipsoidal knob 16 extends substantially perpendicular tothe longitudinal axis 14 of the shaft 12 thereby preventingoverinsertion thereof.

[0025] As a result of this configuration, the region of strongesturethral pressure contributes substantially to the retention of thesuppository within the urethra. In order for the suppository to bewithdrawn, the force applied to the suppository must overcome theincrementally increasing resistance offered by the region of greatesturethral pressure on the increasing diameter of the shaft 12. Thisinterplay between the region of greatest urethral pressure and narrowestshaft diameter yields a significant improvement over urethralsuppositories found in the prior art with respect to the retention ofthe suppository within the urethra. Accordingly, the precise delivery oftherapeutic agents to and absorption by the mucosal lining of theurethra is advantageously achieved.

[0026] The ellipsoidal knob 16 also contributes to the anchoring of thesuppository within the urethra. Insofar as the major axis 17 of the knob16 extends substantially perpendicularly to the longitudinal axis 14 ofthe shaft 12, and is sized to prevent insertion into the urethra, theknob 16 serves to prevent the advance of the suppository into thebladder. More specifically, the inwardly curved surface 18 of the knob16 which extends circumferentially about the second end 15 of the shaft12, as shown in FIG. 2, prevents overinsertion of the suppository by itscontact with the urethral orifice (not shown). Moreover, due to itsellipsoidal shape, the knob 16 is easily palpable by the personperforming the insertion. If subsequent manipulation is required, eitherto effect repositioning or early withdrawal, the knob 16 provides meansfor grasping the suppository readily. Finally, as a result of thesubstantially ellipsoidal shape of the knob 16, the suppository iscompatible with the external anatomy of the human female. Morespecifically, the ellipsoidal nature of the knob 16 permits thealignment of the major axis 17 with the contours of the labia minora ofthe patient so as to afford greater comfort in the use of thesuppository.

[0027] It will be understood that the dimensions of the various portionsof the suppository of the present invention are important to thesuccessful practice of the invention. That is, the suppository must beof such a size that it is properly retainable within the urethra whilenot be so large as to cause undue discomfort to the patient duringinsertion and use. Within such bounds, however, and depending on theparticular dimensions of the urethra into which the suppository will beinserted, variations in the dimensions of the various portions of thesuppository may occur.

[0028] In certain preferred embodiments it has been found that the shaftof the suppository will have an longitudinal axial length of about 3.5to about 5 centimeters, preferably about 4 to about 4.5 centimeters, adiameter at the first end thereof of about 0.8 to about 1.5 centimeters,preferably about 0.8 to about 1.2 centimeters, and a diameter at thesecond end thereof of about 0.4 to about 1 centimeters, preferably about0.5 to about 0.7 centimeters. In such preferred embodiments, theellipsoidal knob will have a major axis of about 1 to about 2centimeters, preferably about 1.3 to about 1.7 centimeters.

[0029] With respect to the manner in which the therapeutic agents andthe biocompatible carrier medium are combined in the suppository of thepresent invention, the therapeutic agent loading level for a givensuppository will vary in accordance with, among other things, whethersuch therapeutic agent is chemically bound to the selected biocompatiblecarrier medium, physically mixed therewith prior to formation into asuppository, or coated on the surface thereof after formation into asuppository or combinations thereof. For those embodiments in which thetherapeutic agent is chemically bound to the selected biocompatiblecarrier medium, the concentration of the therapeutic agent can be ashigh as the stoichiometric ratio of one therapeutic agent molecule perbiocompatible carrier medium bonding site.

[0030] For those embodiments in which the therapeutic agent isphysically mixed with the selected biocompatible carrier medium prior toformation into an urethral suppository or applied as a coating on apreformed urethral suppository, the concentration of the therapeuticagent will vary in accordance with the particular agents that areemployed and the application for which the suppository is used. Incertain embodiments, the therapeutic agent will be applieddifferentially to the surface of the biocompatible carrier medium. Morespecifically, in embodiments in which the therapeutic agent forms acoating on the surface of the biocompatible carrier medium which hasalready been formed into a suppository, the concentration of thetherapeutic agent will vary along the length thereof. In this manner,the precise delivery of different amounts of a therapeutic agent todifferent portions of the urethra may be realized. In any event, thedesired amount of a particular therapeutic agent to be used, and thepreferred manner in which the therapeutic agent is combined with theselected carrier medium will be readily ascertainable by one of ordinaryskill in the art for each particular application.

I claim:
 1. A method for delivering a therapeutic agent to the urethra,bladder and related structures comprising the steps of: providing asuppository comprising one or more therapeutic agents and abiocompatible carrier medium and shaped to be capable of cooperatingwith the action of the periurethral musculature to retain thesuppository within the urethra; inserting the suppository into theurethra; and retaining the suppository within the urethra by the actionof the periurethral musculature for a period of time sufficient topermit the therapeutic agent to diffuse substantially into the urethra.2. The method of claim 1 wherein the therapeutic agent is selected fromthe group consisting of antibiotics, antimicrobials, antifungal agents,analgesics, anaesthetics, steroidal and non-steroidal antiinflammatoryagents, mucous production stimulators, hormones, anti-spasmodics, orcombinations of two or more of these.
 3. The method of claim 1 whereinthe biocompatible carrier medium is selected from the group consistingof carrageenan, modified celluloses, poly(vinyl alcohol),poly(vinylpyrrolidone), polyacrylamide, poly(ethylene glycol),poly(phosphoester-urethanes), ethylenoxide polymers, or combinations oftwo or more of these.
 4. The method of claim 1 wherein the therapeuticagent is disposed throughout the biocompatible carrier medium.
 5. Themethod of claim 1 wherein the therapeutic agent is applied as a coatingto the biocompatible carrier medium.
 6. The method of claim 5 whereinthe therapeutic agent is applied differentially to the biocompatiblecarrier medium.
 7. The method of claim 1 wherein the therapeutic agentis chemically bonded to the biocompatible carrier medium.
 8. The methodof claim 1 wherein the suppository comprises a shaft having a roundedfirst end tapering along a longitudinal axis to a second end, and asubstantially ellipsoidal knob shaped to prevent insertion into theurethra which extends from the second end.
 9. The method of claim 8wherein the substantially ellipsoidal knob has a major axissubstantially perpendicular to the longitudinal axis of the shaft. 10.An urethral suppository shaped to be capable of cooperating with theaction of the periurethral musculature to retain the suppository withinthe urethra comprising: a shaft having a first end and a second end; anda substantially ellipsoidal knob sized to prevent insertion into theurethra which extends from the second end, said shaft and knobcomprising at least one therapeutic agent and a biocompatible carriermedium.
 11. The urethral suppository of claim 10 wherein the shaft has avariable diameter.
 12. An urethral suppository comprising: a shafthaving a rounded first end tapering along a longitudinal axis to asecond end; and a substantially ellipsoidal knob extending from thesecond end of the shaft and sized to prevent insertion into the urethra,said shaft and knob comprising at least one therapeutic agent and abiocompatible carrier medium.
 13. The urethral suppository of claim 12wherein the substantially ellipsoidal knob has a major axissubstantially perpendicular to the longitudinal axis of the shaft. 14.The urethral suppository of claim 12 wherein the therapeutic agent isselected from the group consisting of antibiotics, antimicrobials,antifungal agents, analgesics, anaesthetics, steroidal and non-steroidalanti-inflammatory agents, mucous production stimulators, hormones,anti-spasmodics, or combinations of two or more of these.
 15. Theurethral suppository of claim 12 wherein the biocompatible carriermedium is selected from the group consisting of modified celluloses,poly(vinyl alcohol), poly(vinylpyrrolidone), polyacrylamide,poly(ethylene glycol), poly(phosphoester-urethanes), ethylenoxidepolymers, or combinations of two or more of these.
 16. The urethralsuppository of claim 12 wherein the therapeutic agent is disposedthroughout the biocompatible carrier medium.
 17. The urethralsuppository of claim 12 wherein the therapeutic agent is applied as acoating to the biocompatible carrier medium.
 18. The method of claim 17wherein the therapeutic agent is applied differentially to thebiocompatible carrier medium.
 19. The urethral suppository of claim 12wherein the therapeutic agent is chemically bonded to the biocompatiblecarrier medium.